Faculty of Health Sciences, Nord University, 7801 Namsos, Norway; University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.
University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.
Bioorg Med Chem. 2020 May 15;28(10):115461. doi: 10.1016/j.bmc.2020.115461. Epub 2020 Mar 27.
Cyclin-dependent kinase 8 (CDK8) plays a vital role in regulating cell transcription either through its association with the mediator complex or by the phosphorylation of transcription factors. CDK8-mediated activation of oncogenes has proved to be important in a variety of cancer types including hematological malignancies. We have designed and synthesized a series of new synthetic steroids. The compounds were evaluated as CDK8 inhibitors in vitro. The three most potent compounds exhibit K-values towards CDK8 in the low nanomolar range (3.5-18 nM). Furthermore, the compounds displayed selectivity for CDK8 in a panel of 465 different kinases. The cell studies indicated a selectivity to kill AML-cancer cell lines compared to normal cell lines.
周期蛋白依赖性激酶 8（CDK8）通过与中介复合物的结合或通过转录因子的磷酸化在调节细胞转录中发挥重要作用。CDK8 介导的癌基因激活已被证明在多种癌症类型中很重要，包括血液系统恶性肿瘤。我们设计并合成了一系列新的合成甾体。这些化合物在体外被评估为 CDK8 抑制剂。三个最有效的化合物对 CDK8 的 K 值在低纳摩尔范围内（3.5-18 nM）。此外，这些化合物在 465 种不同激酶的组合中表现出对 CDK8 的选择性。细胞研究表明，与正常细胞系相比，这些化合物对 AML 癌细胞系具有选择性杀伤作用。
